According to the World Health Organization, cancer is a global pandemic that causes nearly 7 million deaths each year worldwide. That number is expected to reach 10 million by the year 2020. Traditionally, cancer is treated using a variety of modalities including surgery, radiation therapy, and chemotherapy. The choice of treatment depends upon the type, location, and dissemination of the cancer. However, these modalities have proven to be relatively ineffective.
B7-1 and B7-2 belong to the B7 Superfamily To date, there are ten known members of the B7 superfamily: B7.1 (CD80), B7.2 (CD86), the inducible co-stimulator ligand (ICOS-L/B7-H2), the programmed death-1 ligand (PD-L1/B7-H1), the programmed death-2 ligand (PD-L2/B7-DC), B7-H3 (CD276), B7-H4 (B7x/B7-S1), B7-H5 (Vista), natural killer cell cytotoxicity receptor 3 ligand (NCR3-LG1/B7-H6), and HERV-H LTR-associating protein 2 (HHLA2/B7-H7) all of which regulate T-cell activation and tolerance. See Greenwald, R. J. et al. The B7 family revisited. Ann. Rev. Immunol. (2005) 23:515-548; Korman, A. J. et al. Adv. Immunol. (2007) 90:297-339; Zang, X. et al. Clin Cancer Res (2007) 13(18):5271-5279; Agarwal, A. et al. Curr. Opin. Organ Transplant. (2008) 13:366-372; Wang, L. et al. J. Exp. Med. (2011) 208(3):577-592; and Zhao, R. et al., HHLA2 is a member of the B7 family and inhibits human CD4 and CD8 T-cell function, PNAS (2013).
B7 superfamily members also belong to the immunoglobulin superfamily and contain an immunoglobulin-V-like (IgV) and an immunoglobulin-C-like (IgC) domain. See Sharpe, A. H. et al., The B7-CD28 Superfamily, Nature Rev. Immunol. (2002) 2:116-126. The IgV and IgC domains of B7 superfamily members are each encoded by single exons, with additional exons encoding leader sequences, transmembrane and cytoplasmic domains. The cytoplasmic domains are short, ranging in length from 19 to 62 amino-acid residues and can be encoded by multiple exons. See Collins, M. et al., Genome Biol. (2005) 6:223.1-223.7. Members of the B7 family are predicted to form back-to-back, non-covalent homodimers at the cell surface, and such dimers have been reported for B7-1 (CD80) and B7-2 (CD86). See Greene, J. L. J. Biol. Chem. (1996) 271:26762-26771; Ikemizu, S. et al. Immunity (2000) 12:51-60; and Greenwald R. J. Annu. Rev. Immunol. (2005) 23:515-548. Further, alternative spliced forms have been observed for various B7 members, including PD-L2, ICOS and B7-H3. See He, X-H. Acta Biochimica et Biophysica Sinica (2004), 36(4):284-289; Hofmeyer, K. A. PNAS (2008) 105(30):10277-10278; and Carreno, B. M. Annu. Rev. Immunol. (2002) 20:29-53.
B7-H4 (also known as B7x or B7S1) is a type I transmembrane protein belonging to the B7 superfamily B7-H4 is hypothesized to be a regulator of antitumor responses, and exploited by tumors to evade immune clearance. The mechanism(s) of action of B7-H4 signaling in T and B-cell activation, and the role of B7-H4 in modulating anti-tumor immune responses is still being unraveled.